|Year : 2020 | Volume
| Issue : 1 | Page : 104-110
Comparative study of statin therapy effects on patient outcome when continued or initiated following an intracerebral hemorrhage
Waleed S Abdelhady Mohamed
Department of Critical Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||08-Jan-2019|
|Date of Acceptance||25-Sep-2019|
|Date of Web Publication||16-Apr-2020|
MD Waleed S Abdelhady Mohamed
Source of Support: None, Conflict of Interest: None
Introduction Intracerebral hemorrhage (ICH) is a neurologic injury resulting in significant morbidity and mortality. Despite clear benefits of statins in ischemic stroke, post-hoc analyses of some studies suggest there may be a link between statin therapy and development of ICH.
Aim The aim of this study was to compare and evaluate the effects of statins therapy when continued or initiated following ICH on patients’ prognosis and outcome.
Patients and methods This study was conducted on 60 adult patients of both sexes who presented with recent ICH and were admitted to Critical Medicine Department, Alexandria Main University Hospital. All cases were subjected to history taking from the patient or next of kin, including age, sex, previous use of statins, associated medical diseases, acute physiology and chronic health evaluation II and sequential organ failure assessment score, and multislice computed tomography on brain. Patients were classified into three groups: control group I (20 patients) was not receiving previous statin therapy and they did not receive statin therapy during this study, study group II (20 patients) was not receiving previous statin therapy and they received statin therapy in the form of atorvastatin 20 mg once daily, and study group III (20 patients) was receiving previous statin therapy and they continued on statin therapy in the form of atorvastatin 20 mg once daily.
Results The patients showed nonsignificant difference regarding demographic data, hemodynamics, arterial blood gases, and outcome.
Discussion In our study, it was found that there was a decrease in mortality in all the study groups treated with statin, but this decrease was nonsignificant. The duration of hospital stay showed a significant decrease in both groups II and III.
Conclusion The use of statin therapy when continued or initiated following an ICH on patients has no significant effect on prognosis and outcome of these patients.
Keywords: critical medicine, intracerebral hemorrhage, statins, stroke
|How to cite this article:|
Abdelhady Mohamed WS. Comparative study of statin therapy effects on patient outcome when continued or initiated following an intracerebral hemorrhage. Res Opin Anesth Intensive Care 2020;7:104-10
|How to cite this URL:|
Abdelhady Mohamed WS. Comparative study of statin therapy effects on patient outcome when continued or initiated following an intracerebral hemorrhage. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 Jun 2];7:104-10. Available from: http://www.roaic.eg.net/text.asp?2020/7/1/104/282587
| Introduction|| |
Intracerebral hemorrhage (ICH) accounts for 10–20% of all stroke cases worldwide . The overall global incidence of ICH is estimated at 24.6 per 100 000 person-years . Significant risk factors for ICH include hypertension, amyloid angiopathy, and older age . Other risk factors include male sex, smoking, diabetes, alcohol intake, cocaine hydrochloride use, and use of antiplatelet or anticoagulant medications ,,. Compounding risk factors are likely to increase the risk of a patient having ICH. ICH commonly occurs in the cerebral lobes, basal ganglia, thalamus, brain stem, and cerebellum. Hemorrhage results from rupture of small penetrating arteries originating from basilar arteries or the anterior, middle, or posterior cerebral arteries. ICH carries a significant mortality risk with 1-year survival estimated at 46% and 5-year survival estimated at 29% . Given the high degree of morbidity and mortality associated with ICH, evaluation of therapies that may have neuroprotective effects is of increasing interest to clinicians.
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, provide cholesterol-lowering effects through competitive, reversible inhibition of HMG-CoA reductase; the rate limiting step in cholesterol biosynthesis ,. This mechanism is the primary driver for the observed reduction in cardiovascular events and ischemic stroke in patients with coronary artery disease . In addition to their cholesterol-lowering effects, statins also have pleotropic effects, including anti-inflammatory, antithrombotic, antioxidative, and neuroprotective effects that have all been demonstrated in animal models and/or patients ,. The primary aim of this study is to evaluate the effects and outcomes associated with statin use in relation to ICH.
Although all statins share the same primary mechanism of action through the competitive, reversible inhibition of HMG-CoA reductase, there are many differences within this class of drugs. There are seven statins currently available in the USA: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Statins have a high bioavailability and are currently only available in oral formulations. The observed differences in drug pharmacology may ultimately affect the possible risks and benefits of statin therapy in ICH . Statin penetration across the blood–brain barrier and into the cerebral cortex is directly related to the lipophilic properties of each statin . A murine model evaluated simvastatin, lovastatin, and pravastatin concentrations within the cerebral cortex. This model showed higher concentrations of simvastatin and then lovastatin followed by pravastatin. These results are consistent with simvastatin and lovastatin being the most lipophilic statins ,. In addition to the pharmacokinetic properties of statins, the relative potency of low-density lipoprotein reduction should also be considered. Two landmark trials evaluated the relative potency of statin therapies. Potency was determined by percent change in low-density lipoprotein from baseline. Rosuvastatin was found to be the most potent followed by atorvastatin, pitavastatin, simvastatin, lovastatin, pravastatin, and finally fluvastatin .
| Aim|| |
The aim of this study was to compare and evaluate the effects of statin therapy when continued or initiated following an ICH on patients’ prognosis and outcome.
| Patients and methods|| |
This study was conducted on 60 adult patients who presented with recent ICH and were admitted to Critical Medicine Department, Alexandria Main University Hospital.
Informed consent was taken from the patients or next of kin, and approval of the faculty ethics committee was obtained.
- All patients admitted to critical medicine department for presenting with ICH diagnosed by multislice computed tomography, recently either on previous statin therapy in the past 6 months or not received statin therapy at all, were included in the study.
The following were the exclusion criteria:
- Patients with history of hepatic diseases.
- Patients with history of renal diseases.
- Patients with history of musculoskeletal problems.
- Traumatic brain injury (GCS <8) or death anticipated within 12 h.
Patients included in this study were classified at random using closed envelope method into three groups:
- Control group I: 20 patients who were not receiving previous statin therapy and they did not receive statin therapy during this study.
- Study group II: 20 patients, who were not receiving previous statin therapy and they received statin therapy in the form of atorvastatin 20 mg once daily.
- Study group III: 20 patients who were receiving previous statin therapy and they continued on statin therapy in the form of atorvastatin 20 mg once daily.
All patients included in this study were subjected to the following:
- History taking from the patient or next of kin, including age; sex; associated medical diseases, for example, cerebrovascular stroke, diabetes mellitus, cardiovascular heart disease, renal disease, liver impairment, or arterial hypertension; and drug (especially statins) history.
- On admission, clinical examination, multislice computed tomography on brain, and evaluation of all systems of the body were done, and the severity of illness was assessed by acute physiology and chronic health evaluation II score.
- Routine laboratory studies were carried out on admission and followed up daily including the following:
- Complete blood picture.
- Arterial blood gases and hypoxic before and after treatment.
- Random serum glucose.
- Conventional treatment of ICH.
- The study drug would be discontinued or interrupted if following instances occurred:
- Any of its serious adverse reactions occurred.
- Deterioration of level of consciousness owing to recently reported or increase in previous hemorrhage.
- Hemodynamic assessments included the following:
- ECG was done on admission and when needed.
- Mean arterial blood pressure and pulse rate were noninvasively monitored, and data were continuously monitored during the study period, the same with the pulse rate, and any increase more than 20% of normal value was recorded using ‘Dräger − infinity kappa’ or any suitable available ICU monitor.
- Radiological studies were as follows:
- Plain radiography chest was done on admission and whenever needed to spot any lung infiltrate.
- Multislice computed tomography brain on admission, follow up at least within 48 h and when indicated.
- Prognosis and outcome was assessed with respect to the following:
- Length of ICU or hospital stay (days).
- ICU and hospital mortality.
- Sequential organ failure assessment score.
- End points of the study were as follows:
- Improvement and discharge from ICU.
| Results|| |
The demographic data (age and sex) were matched in the three studied groups without significant difference. The associated medical comorbidities showed insignificant difference among the three studied groups. The acute physiology and chronic health evaluation II score on admission was similar in the three studied groups, and there was no significant difference among the three studied groups. Random blood surge showed no significant difference among the three studied groups ([Table 1]).
Regarding blood gases, pH, PaCO2, SaO2, and HCO3 showed significant difference in the same group, but no significant difference among the three studied groups before and after treatment. It was found that there was a significant improvement after treatment in both groups II and III, whereas group I (control) showed insignificant difference.
Hemodynamic parameters showed insignificant difference among the three studied groups before treatment and after treatment.
The outcome showed insignificant difference among the three studied groups regarding mortality, sequential organ failure assessment score, and ICU stay, whereas the hospital stay showed a significant decrease in both groups II and III ([Table 2],[Table 3],[Table 4], [Figure 1] and [Figure 2]).
| Discussion|| |
In our study, it was found that there was a decrease in mortality in both groups treated with low-dose statin, but this decrease was nonsignificant. The length of hospital stay showed a significant decrease in both groups II and III. This was agreed with the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, which evaluated high-dose (80 mg) atorvastatin compared with placebo for incidence of nonfatal and fatal stroke in patients with a history of transient ischemic attack or stroke in the previous 6 months. A post-hoc analysis of treatment effect on type of stroke showed a significant increase in hemorrhagic stroke in the high-dose atorvastatin group . Further evaluation of this cohort found no difference in severity or outcomes when comparing patients in both arms having hemorrhagic stroke .
A recent large population-based case–control study from Sweden, including ICH cases (n=7696) and matched stroke-free controls (n=14 670), evaluated the association between chronic statin therapy and ICH. No difference in risk for development of ICH in the unadjusted model was found. In the adjusted model, statins were found to be protective against ICH for concomitant drug use and comorbid diseases (odds ratio=0.68, 95% confidence interval=0.63–0.74) . A follow-up retrospective analysis showed chronic statin users had less severe ICH . Several well-controlled meta-analyses reported no difference in rates of ICH in patients receiving statin therapy compared with no statin therapy ,,. Pre-ICH therapy was associated with increased probability of positive functional outcomes, based on modified Rankin Scale score and Glasgow Outcome Scale . A meta-analysis performed by McKinney et al.  included 31 randomized-control trials with 182 803 patients, including patients from the SPARCL study. Results demonstrated no significant difference in incidence of ICH observed in the active statin treatment group. The analysis did find significant reductions in total stroke and all-cause mortality in the active statin therapy group. Current guidelines do not recommend avoiding statin therapy owing to a potential risk of ICH .
There are currently no prospective randomized trials that are adequately powered to evaluate the effect of starting statin therapy on major clinical outcomes following ICH. Several retrospective meta-analyses and database studies have demonstrated improved mortality and functional outcomes with statin therapy following ICH. These outcomes are notable as the outcomes remained significant after adjustment for prehospital statin use within their statistical evaluations ,,. Unfortunately, none of the analyses clearly defined the initiation time frame of statin therapy following ICH, so the window of opportunity for initiation after ICH requires further refinement.
The role of initiating statin therapy following ICH in statin-naive patients is not well defined. Two retrospective database reviews evaluated patients with no prehospital statin therapy. The first database review (n=8332) demonstrated that early statin use did not increase the risk of recurrent ICH (hazard ratio=1.044, 95% confidence interval=0.812–1.341) ,. Although the data are not conclusive, it does suggest that initiation of statin therapy after ICH may be reasonable in patients where the potential benefits outweigh the risks.
Discontinuation of statin therapy following ICH has been significantly associated with increased 30-day mortality ,. Additionally, discontinuation of statin therapy following ICH was significantly associated with decreased favorable discharge when controlling for severity of illness . These outcomes should be viewed with caution because there are potentially significant confounders associated with discontinuation of statin therapy, namely, the withdrawal of aggressive management and transition to comfort care measures. Prospective trials are needed to adequately evaluate the effects of discontinuation of statin therapy in the setting of acute ICH. Until further evidence is generated, it appears reasonable to continue statin therapy in patient with ICH unless contraindications to therapy are noted.
Statin use has been shown to reduce primary and secondary cardiovascular events, reduce coronary death rate, reduce total fatal and nonfatal stroke, and improve functional outcomes following an ischemic stroke ,,,. Despite the many benefits of statin therapy, there has been a signal toward increased rates of ICH with statin therapy. As discussed previously, data from the SPARCL trial showed a 16% decrease in total stroke, but a post-hoc analysis showed a significant decrease in ischemic stroke events and an increase in ICH ,.
The mechanisms by which statin therapy may increase hemorrhage risk are unclear. A previous study described an inverse relationship to serum lipid levels and risk for ICH, showing 6-year risk of death from intracranial hemorrhage was three times more likely in men with serum cholesterol levels less than 160 mg/dl . Konishi et al.  proposed that decreased serum cholesterol levels contribute to the development of fragile cerebrovascular endothelium, eventually leading to the development of angionecrosis and cerebral hemorrhage in the setting of hypertension.
To date, there are no large prospective trials evaluating the safety and efficacy of statin therapy in ICH. Despite the retrospective signal for increased risk of ICH from the SPARCL trial, these findings were not further validated in several meta-analyses. The combination of secondary microvascular injury and high-dose atorvastatin therapy with lowered total cholesterol levels may have increased risk of ICH not seen in other prospective statin trials.
Further studies are needed to elucidate if there is a clinically relevant risk of decreased total cholesterol levels and development of ICH. Evaluation is also needed for specific patient cohorts who would benefit from statin continuation or discontinuation in relation to ICH. In particular, the effect of statin therapy in older patients, men versus women, patients with specific comorbidities (e.g. cardiovascular and diabetes), and those receiving a large number of concomitant or interacting medications may be important to analyze the effectiveness and risk for ICH in statin users. Given the paucity of clinical data providing clear direction on the use of statins in ICH, careful evaluation of clinically relevant literature, evidence-based national guidelines, and patient risk versus benefit should be considered when utilizing statin therapy .
In a population-based study of community-acquired pneumonia, Majumdar and colleagues found that statin users were less likely to die or to be admitted to the ICU than non-users [50/325 (15%) vs. 574/3090 (19%)]. As subjects of a population-based study, the patients of Majumdar et al.  were relatively healthy users compared with our population. Additionally, it remains unclear whether these findings, which were observed in patients with community-acquired pneumonia, are applicable to all critically ill patients. Yang et al.  conducted a retrospective study and found no difference in mortality between the two groups, despite the presence in patients in the statin group of less organ dysfunction, lower APACHE II scores, less inotropic support, and less shock.The lack of benefit observed in these studies might be related to differences in the patient disease mix, severity of illness, or statin type and dose .
| Conclusion|| |
The use of statin therapy when continued or initiated following an ICH has no significant effect on prognosis and outcome. Despite proposed pharmacologic mechanisms for increased risk of ICH, the increasing body of clinical evidence does not support the theory that statins significantly increase the rates of ICH. Further studies are required to delineate which patients with ICH would benefit from statin therapy. Decisions to use statin therapy in patients with ICH should be decided on an individual patient basis. Statin therapy should be prescribed in situations where the potential to maximize benefits and minimize risk is greatest.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]